American Journal of Medical Genetics 46:263-267 (1993)
Mixed Gonadal Dysgenesis: Clinical, Cytogenetic, Endocrinological, and Histopathological Findings in 16 Patients
Juan Pablo Mendez, Alfred0 Ulloa-Aguirre, Susana Kofman-Alfaro, Osvaldo Mutchinick, Carlos Fernhdez-del-Castillo, Edgardo Reyes, and Gregorio Perez-Palacios Departments of Reproductive Biology (J.P.M., A.U-A., G.P.P.), Genetics (OM.) , Gynecology (C.F-d-C.) and Pathology (E.R.), Instituto Nacwnal de la Nutricwn Salvador Zubiran; and Department of Genetics (S.K-A.), Hospital General de Mtkico, Mexico D.F.
We describe clinical, cytogenetic, endocrine, and histopathological findings in 16 patients with mixed gonadal dysgenesis (MGD). All pa- tients except l presented genital ambiguity and 10 of them had Ullrich-Turner manifesta- tions. The 45,X/46,XY karyotype was the most frequent with a predominance of 45,X cells in both peripheral lymphocytes and gonads. In all cases Mullerian and Wolffian remnants and/or derivatives were found and in some patients both Wolffian- and Mullerian-de- rived structures were identified on the streak or testicular side. Postpubertal patients ex- hibited variable degrees of virilization and all of them had hypergonadotropism coexisting with low to normal baseline serum levels of testosterone; their testicular response to hu- man chorionic gonadotropin (HCG) in terms of testosterone secretion was also variable, ranging from minimal to almost a normal re- sponse. All prepubertal patients but 1 had normal baseline levels of pituitary gonad- otropins and testosterone and their gonadal response to the HCG challenge was highly variable. With the exception of 1 case, who had a 45X/46XY(p - ) karyotype, no correla- tion between the cytogenetic data and degree of external genital ambiguity and the hor- monal findings was observed. Additional in- formation on the specific structural abnor- malities involving the testis-determining gene of the Y chromosome in patients with MGD is needed in order to further understand the
Received for publication June 29,1992; revision received Novem- ber 23, 1992.
Address reprint requests to Juan P. MBndez, Department of Reproductive Biology, Instituto Nacional de la Nutrici6n SZ, Vasco de Quiroga 15, Tlalpan 14000, Mexico D.F., Mexico.
mechanisms responsible for the wide vari- ability characteristic of this disorder. 0 1993 Wiley-Liss, Inc.
KEY WORDS: postpubertal patients, karyo- type, testosterone
INTRODUCTION Mixed gonadal dysgenesis (MGD) encompasses an
heterogenous group of different chromosomal, gonadal, and phenotypic abnormalities characterized by the pres- ence of a testis on one side and a streak or an absent gonad at the other [Davidoff and Federman, 19731, per- sistence of Mullerian duct structures, and a variable degree of genital ambiguity. Ullrich-Turner syndrome stigmata and renal abnormalities may also be found; and some gonadal tumors, such as gonadoblastoma and dysgerminoma are frequently seen in patients with this disorder [Robboy et al., 1982; Rutgers and Scully, 1987; Wallace and Levin, 19901. Even though the characteris- tics of MGD have been extensively described in these studies, in most of them the endocrine findings are unre- ported and comments on the endocrine status of the patients, if included, are fragmentary. Here we analyze the main characteristics found in 16 patients with MGD and attempt to correlate their endocrine profile with the clinical, cytogenetic, and histopathological findings.
SUBJECTS AND METHODS The charts of 16 patients with MGD who were evalu-
ated and treated by the authors between 1980 and 1991 and in which surgical pathology material documented the presence of a testis and a contralateral streak were included in the analysis. None of them had received hormonal preparations as treatment of their condition. The first two cases (Table I) were reported in a previous study of patients with 45,X/46,XY karyotypes [Kofman- Alfaro et al., 19811. All patients had a complete clinical, cytogenetic, and endocrine evaluation which included measurement of the baseline levels of immunoreactive
0 1993 Wiley-Liss, Inc.
TAB
LE I
. C
linic
al, C
ytog
enet
ic, H
isto
path
olog
ical
and
Hor
mon
al F
indi
ngs
in 1
6 Pa
tient
s W
ith M
ixed
Gon
adal
Dys
gene
sis
Age
C
ase
(yr/
mo)
K
aryo
type
a
20/0
6/0
1 /4
2 /9
19/0
7/0
16/0
1 /4
45,X
/46,
XY
45,X
/46,
XY
45,X
/46,
XY
45,X
/46,
XY
45,X
/46,
XY
45,X
/46,
XY
45,X
/46,
XY
p -
45,X
/47,
XY
Y
Ullr
ich-
Tur
ner
stiw
ata
Shor
t le
ft 4
th m
etac
arpu
s an
d m
etat
arsu
s
Low
hai
rlin
e, s
hort
and
w
ebbe
d ne
ck, m
ultip
le
nevi
Fa
cial
asy
mm
etry
, hi
gh
pala
te,
low
hai
rlin
e,
shor
t nec
k Fa
cial
asy
mm
etry
, hi
gh
pala
te
Hig
h pa
late
, low
hai
rlin
e,
mul
tiple
nev
i
Gon
ads
and
inte
rnal
ge
nita
liab
(rig
ht s
ide/
LH
(m
IU/
Ext
erna
l ge
nita
lia
left
sid
e)
ml)
d
Phal
lus
8 cm
, per
inea
l hy
posp
adia
s, n
orm
al
pubi
c ha
ir
Phal
lus
3 cm
, pha
llic
hypo
spad
ias
Phal
lus
2.5
cm,
peri
neos
crot
al
hypo
padi
as
Phal
lus
2 cm
, pen
oscr
otal
hy
posp
adia
s
Phal
lus
10 c
m, p
erin
eal
hypo
spad
ias,
nor
mal
pu
bic
hair
Ph
allu
s 3
cm,
peri
neos
crot
al
hypo
spad
ias
Phal
lus
0.5
cm, f
emal
e
Phal
lus
2.5
cm, p
halli
c hy
posp
adia
s
Ingu
inal
tes
tis,
ep
idid
ymis
, vas
de
fere
ns/S
trea
k,
Fallo
pian
tube
St
reak
, Fal
lopi
an t
ube/
C
rypt
orch
idic
tes
tis,
ep
idid
ymis
, vas
de
fere
ns
Intr
ascr
otal
tes
tis,
ep
idid
ymis
"/St
reak
, Fa
llopi
an t
ube,
ep
idid
ymis
St
reak
, Fal
lopi
an t
ube,
ep
idid
ymis
iInt
rasc
rota
1 te
stis
, epi
didy
mis
' In
tras
crot
al t
esti
s,
epid
idym
is'/S
trea
k,
Fallo
pian
tub
e St
reak
, Fal
lopi
an t
ube,
ep
idid
ymis
hgui
nal
test
is, e
pidi
dym
is
Cry
ptor
chid
ic t
esti
s,
Fallo
pian
tub
e,
epid
idym
is/S
trea
k,
Fallo
pian
tub
e In
tras
crot
al t
esti
s,
epid
idym
is?S
trea
k.
38.0
1.5
1.2
0.8
14.5
1.8
43.0
1.6
FSH
(m
IU/m
l)d
42.0
0.6
0.7
1.0
23.5
0.9
51.5
0.5
Bas
al T
T
post
- (n
g/m
lld
HC
G~
3.
4
0.2
0.3
0.6
4.8
0.2
0.5
0.4
6.2
1.2
2.6
1.3
8.8
1.1
0.9
3.5
__ -
Fa
llopi
an tu
be
9 10
11
12
13
14
15
16
0/11
46
,XY
-
0111
45
,X/4
6,X
Y,id
ic(Y
) -
2010
46
,XY
H
igh
pala
te,
mul
tiple
ne
vi
118
45,X
/46,
XY
B
ilate
ral
shor
t m
etac
arpu
s “c
afe
au
lait”
spo
ts
011
45,X
/46,
XY
Sh
ort a
nd w
ebbe
d ne
ck
216
45,X
/46,
XY
,dic
(Y) -
2710
45
,X/4
6,X
Y,d
ic(Y
) Lo
w h
airl
ine,
sho
rt n
eck,
m
ultip
le n
evi
1/10
45
,X/4
6,X
Y
Low
hai
rlin
e, s
hort
and
w
ebbe
d ne
ck
Phal
lus
4 cm
, pen
oscr
otal
hy
posp
adia
s
Phal
lus
1 cm
, pe
rine
oscr
otal
hy
posp
adia
s Ph
allu
s 4
cm,
peri
neos
crot
al
hypo
spad
ias,
sca
nty
pubi
c ha
ir
Phal
lus
3 cm
, pen
oscr
otal
hy
posp
adia
s
Phal
lus
2.5
cm,
peno
scro
tal
hypo
spad
ias
Phal
lus
2.5
cm,
peno
scro
tal
hypo
spad
ias
Phal
lus
4 cm
, pe
rine
oscr
otal
hy
posp
adia
s, s
cant
y pu
bic
hair
Ph
allu
s 3
cm, p
enos
crot
al
hypo
spad
ias
Stre
ak, F
allo
pian
tube
1 C
rypt
orch
idic
tes
tis,
epid
idym
is
Stre
ak, F
allo
pian
tube
1 In
tras
crot
al t
estis
, ep
idid
ymis
‘ In
guin
al t
estis
, ep
idid
ymis
, vas
defe
rend
stre
ak,
Fallo
pian
tub
e,
epid
idym
is
Stre
ak, F
allo
pian
tub
e/
Intr
ascr
otal
tes
tis,
epid
idym
is‘
Stre
ak, F
allo
pian
tub
e,
epid
idym
islh
guin
al
test
is, e
pidi
dym
is
Stre
ak, F
allo
pian
tube
1 C
rypt
orch
idic
test
is,
Fallo
pian
tub
e,
epid
idym
is
Stre
ak, F
allo
pian
tub
e1
Intr
ascr
otal
tes
tis,
epid
idym
is‘
Ingu
inal
tes
tis,
epid
idym
idst
reak
, Fa
lloD
ian
tube
0.8
0.7
1.4
0.8
32.5
33
.7
4.6
0.5
10.3
2.
1
0.3
1.3
25.1
20
.5
1.6
0.7
0.1
0.6
1.9
1.6
2.2
0.1
1.2
0.9
2.2
2.9
2.3
4.7
4.7
0.9
2.4
3.0
.In p
erip
hera
l ly
mph
ocyt
es.
bAll
pati
ents
pre
sent
ed e
ithe
r in
fant
ile
or r
udim
enta
ry u
teru
s.
‘In a
ll in
tras
crot
al te
stis
onl
y te
stic
ular
bio
psy
was
take
n.
dRef
eren
ce va
lues
: Pos
tpub
erta
l men
, LH
: 3-1
2 m
IU/m
l; FS
H: 1
-5 m
IUlm
l; T:
3.5
-8.0
ngl
ml;
max
imal
T a
fter
HC
G: 9
to 1
6 ng
/ml.
Chi
ldre
n, L
H: 0
.5-5
.0
mIU
/ml;
FSH
: 0.5
-2.5
mIU
1ml;
T: 0
.07-
0.8
ng/m
l; m
axim
al T
aft
er H
CG
: 1.
5-4.
5 ng
/ml.
266 Mendez et al.
serum gonadotropins, 17P-estradiol (E2) and testoster- one (T) as well as gonadal responsiveness to exogenous human chorionic gonadotropin (HCG) [Ulloa- Aguirre et al., 1988a,b]. In 13 cases chromosome analysis was per- formed on both peripheral lymphocytes and cultured biopsies from each gonad, streak and testis, whereas in the remaining 3 cases only on lymphocytes. The exact type of each gonad was determined by the criteria estab- lished by Robboy et al. 119821.
RESULTS AND DISCUSSION Individual clinical traits of the 16 patients analyzed
are shown in Table I. In 10 cases (cases 1, 2, 4-7, 12, 14-16), height was <3rd centile for normal Mexican individuals. Also, 10 of them (8 with short stature) ex- hibited Ullrich-Turner stigmata. Only 3 patients had renal anomalies (cases 5 and 7, horseshoe kidney and case 13, left ureteral stenosis) and in one case (case 15) aortic coarctation was observed. In all cases, except in patient 7, genital ambiguity was found and external genitalia tended to be more masculine than feminine, appearing as a bifid scrotum or rugated labioscrotal folds. All these patients had hypospadias of variable degree (Table I).
Chromosome analysis showed that all patients had a Y chromosome, including 13 with a 45,X/46,XY mosai- cism (4 of them with structural abnormalities of the Y chromosome), 1 with a 45,X/47,XYY mosaicism, and 2 with an apparently normal 46,XY karyotype in lympho- cytes (Table I). In cases 1,3,6,7, and 10 the proportion of 45,X and 46,XY cells observed in blood and gonads was similar (45,X cells in blood 74-92, in gonads 75-91; 46,XY cells in blood 6-26, in gonads 6-25), whereas in cases 2 ,4 ,5 ,8 , 12, 14, and 15 the 45,X cells exhibited a higher frequency in the gonadal tissue (54-100%) than in blood (10-48%), reaching 100% in cases 2 and 15. In case 12 a complex mosaicism (45,X/46,XY/47,XY +mar) was restricted to the gonads, and in case 9,100% of XY cells were found in both the gonads and blood.
All patients had persistent Mullerian structures which ranged from a normal to an infantile or rudimen- tary uterus. A Fallopian tube always accompanied the streak gonad. Interestingly, in 2 of the 4 patients with cryptorchidism (cases 7 and 14), a Fallopian tube was also found adjacent to the testis; all 4 of these cases had a well-formed ipsilateral epididymis. In 5 of the 16 pa- tients, the opposite streak gonad also was associated with an epididymis. Gonadal tumors were found in 3 patients (cases 1 and 7, unilateral gonadoblastoma; and case 11, a left gonadoblastoma and a right seminoma with areas of embryonal carcinoma).
In all postpubertal patients (cases 1, 5,7, 11, and 15) serum levels of FSH and LH were significantly in- creased (Table I) with the exception of case 5, who showed serum LH concentrations marginally elevated (14.5 mIU/ml). In this latter patient, serum T was within the normal range, whereas in the remaining postpubertals the concentration of this androgen was decreased. Administration of HCG induced significant serum T increments in subjects 1 ,5 , and 15 and margi- nal rises in subjects 7 and 11. The lowest baseline and HCG stimulated serum T concentrations were exhibited
by patient 7, who had a female phenotype, a low percent- age of XY cells in both blood (8%) and gonads (9%), and structural abnormalities on the short arm of the Y chro- mosome (p-). Nine out of 11 prepubertal patients ex- hibited normal baseline levels of serum LH, FSH, and T. In case 13 (1 month old), serum LH and T concentrations were elevated; this finding agrees with previous reports showing that neonates may normally exhibit increased values of these hormones [Winter et al., 19761. The re- maining case (case 12) presented serum LH levels in the upper limit of normality and increased baseline T con- centrations. As it has been reported in normal children [Ulloa-Aguirre et al., 19851, prepubertal patients with MGD exhibited heterogeneous T responses to HCG ad- ministration which ranged from net T increments of 0.7-0.8 ng/ml (cases 4 and 14) to increments up to 3.1 ng/ml (cases 8 and 12). In all prepubertal and postpuber- tal cases serum E, was <15 pgtml. With the exception of case 7, we did not find any clear relationship between the hormonal profile and the clinical (e.g., degree of genital ambiguity), cytogenetic, and histopathologic changes exhibited by both groups of patients with MGD.
The overall findings strikingly illustrate that the functional deficit elicited by the abnormal gonadal de- velopment in MGD is expressed as incomplete produc- tion and/or action of the Mullerian inhibiting hormone (MIH) and T, with concomitant incomplete inhibition of Mullerian development and an impaired differentiation of the Wolffian duct derivatives and external genitalia, thus resulting in a marked asymmetry of the internal and external genitalia. The 14 mosaic patients pre- sented marked phenotypical and histopathological sim- ilarities irrespective of the proportion of cells lacking or having a structurally normal or abnormal Y chromo- some. All 14 cases had uterus, Fallopian tube, and epi- didymis and in 3 of them a vas deferens was also found on the testicular side. The finding of Wolffian deriva- tives in the streak side of 5 cases suggests either that the in utero production of T by the contralateral testis was adequate to induce some Wolffian duct differentiation in both sides or that the embryonic streak produced margi- nal but sufficient amounts of T or its androgenic pre- cursos to allow some ipsilateral development of Wolffian derivatives [Judd et al., 19701. Conversely, in the 2 cases exhibiting both Fallopian tube and epididymis on the testicular side (cases 7 and 141, a more severe defect in the production and/or action of MIH than that presented by the patients without this Mullerian derivative may be postulated.
The elevated baseline levels of serum gonadotropins in all postpubertal cases indicated the existence of an impaired testicular function of variable degree. In fact, a wide spectrum in T production and reserve was ob- served, ranging from severe (case 7) to mild (case 1) or minimal (case 5 ) Leydig cell dysfunction (cases 1 and 5). The presence of severe external genital ambiguity in all patients, including cases 1 and 5 who presented almost normal virilization at puberty, suggests that even in those cases with minimally impaired T production, the amount of this androgen produced in utero (particularly between the 8th and 12th weeks of gestation) was insuf- ficient to promote, via 5ct-dihydrotestosterone, a com-
Mixed Gonadal Dysgenesis 267
plete differentiation of external genitalia. Thus, in con- trast to the normal testis, in MGD the ability of the dysgenetic testis to virilize a t adolescence can not be taken as a recapitulation of its capacity to masculinize the external genitalia in utero. With the exception of case 13, all prepubertal cases exhibited normal serum levels of both gonadotropins; the presence of a dysgene- tic testis possessing some residual function might ex- plain this finding, particularly considering that during infancy the negative feedback involving the gonads and the hypothalamic-pituitary axis operates at a high sen- sitive level [Conte et al., 19751.
This study confirms and extends previous reports [Davidoff and Federman, 1973; Donahoe et al., 1979; Kofman-Alfaro et al., 1981; Robboy et al., 1982; Wallace and Levin, 19901 and indicates that in most patients with MGD the hormonal profile does not correlate with the clinical, cytogenetic, and histopathological charac- teristics of the disease. Further elucidation on the spe- cific structural abnormalities involving the testis-deter- mining gene on the Y chromosome in patients with MGD and which almost invariably lead to an incomplete differentiation of the somatic sex structures, will un- doubtedly allow a better understanding of the mecha- nisms responsible for the wide heterogeneity character- istic of this particular disorder.
ACKNOWLEDGMENTS This study was supported by the Rockefeller Founda-
tion (New York, NY) and the Special Programme on Research, Training and Development in Human Repro- duction, WHO (Geneva, Switzerland).
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